Well-designed experiments are proposed to prove or disprove the following general hypothesis: Measureable physicochemical properties are contributing parameters in the quantification of bioactivity and bioaccumulation of lipophilic xenobiotics. The proposed studies will measure these physicochemical properties using systems which do not involve animal experimentation. Bioaccumulation--Lipophilicity. It is hypothesized that the initial distribution of lipophilic xenobiotics in blood plasma lipoprotein fractions is an important parameter in the quantification of the bioaccumulation in tissues. We propose to measure the partition coefficients of selected PCB congeners using novel physiologically relevant model systems that include many of the important biological parameters absent in current methods and to validate them by correlating the partition coefficients obtained from data previously collected in a case-controlled study of human subjects exposed to PCBs. Bioactivity--Dynamic Shape and Structural Polarity. It is hypothesized that the dynamic shape and the chemical polarity of a xenobiotic are physicochemical parameters important to its binding to specific proteins and its passive or facilitated diffusion across membranes. These physicochemical parameters will be correlated to published information on the metabolism and the induction of microsomal enzymes by selected PCBs, and used to predict corresponding information for PCBs of unknown activity. These are the first times that lipoprotein micellar pseudophase liquid chromatography have been proposed to study the distribution of chemical agents between hydrophobic and hydrophilic physiological systems and that gas chromatography has been proposed to study bioactivity by measurement of enthalpy and entropy. Partition coefficients, enthalpy and entropy can only be accurately and relevantly modelled using chromatography, since the physiological system being modelled is a dynamic one.
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